Paper

MYCN mediates cysteine addiction and sensitizes to ferroptosis

Kreth, Jochen, Kai Oliver Henrich, Herrmann, Carl, Alborzinia, Hamed, Gartlgruber, Moritz, Hess, Elisa M, Buettner, Michael, Steinhauser, Sebastian, Hartlieb, Sabine, Poschet, Gernot, Florez, Andres F, Westermann, Frank, Stresemann, Carlo, Hoefer, Thomas, Ziehm, Matthias, Dreidax, Daniel, Reiling, Jan H, Gogolin, Sina, Paul, Franziska, Shao, Chunxuan, Ido Amit, Fischer, Matthias, Shaikhkarami, Marjan, Brueckner, Lena M, Michal Nadler Holly, Nicke, Barbara, Woelfl, Stefan, Bell, Emma, Selbach, Matthias

2021

Overview

Aberrant expression of MYC family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYC induces massive lipid peroxidation upon depletion of cysteine, the rate-limiting amino acid for glutathione biosynthesis and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. In MYCN-amplified childhood neuroblastoma, MYCN mediates resistance to ferroptosis by activating transsulfuration of methionine to cysteine. MYCN may contribute to spontaneous tumor regression in low-risk neuroblastomas by promoting ferroptosis in cells with epigenetically silenced cystathionine-beta-synthase, the rate-limiting enzyme for transsulfuration. We identified enzymes and antiporter proteins crucial to ferroptotic escape, providing multiple previously unknown sites that may be acted on therapeutically. Competing Interest Statement The authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Addictions / Amino acids / Antioxidants / Apoptosis / Cancer Biology / Cell death / Children / Cysteine / Ferroptosis / Glutathione / Lipid peroxidation / Methionine / Myc protein / Neuroblastoma